HEPATITIS B AND C AND ELEVATED LIVER TRANSAMINASE LEVELS
| NEW TREATMENTS FOR CHRONIC HEPATITIS B AND C —Paul J. Pockros, MD, Head, Division of Gastroenterology/Hepatology,
Scripps Clinic, La Jolla, CA
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Hepatitis C
| Subtypes of hepatitis C virus (HCV): genotype 1—1a or 1b; ≈75% of patients in United States; most refractory to
interferon (INF); genotypes 2 and 3—less refractory to INF; most of patients in Europe, only ≈25% of patients in
United States; genotype 6—less common; high prevalence in southern California (large Vietnamese population); easier
to treat than genotype 1 but requires longer duration of treatment
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| Hepatitis C infections: chronic 80% of time; virus down-regulates INF-stimulating genes in human hepatocyte, resulting
in inability to clear virus; 20% of patients do not become chronically infected; chronic infections—1) one third of
patients have stable disease, usually with no serious morbidity or mortality; patients more often women <40 yr of age at
time of infection, do not drink alcohol, and thin; 2) one third of patients have aggressive disease and develop cirrhosis
rapidly (in 10-20 yr); patients more often men >40 yr of age when infected, drink >50 g of alcohol daily, and overweight
or obese; 3) 40% progress slowly (over 30-40 yr) to serious liver disease; development of serious liver disease increasing;
antiviral therapy successful in ≈50% of patients
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| Factors associated with worse disease: alcohol consumption (>30 g daily in men, >20 g daily in women); infection
at age >40 yr; male sex; HIV or hepatitis B coinfection; immunosuppression; no direct association between serum alanine
aminotransferase (ALT) levels and amount of injury to liver; viral load predictive of response to therapy but not of damage
to liver; mode of transmission and genotype do not influence progression
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| Future burden of disease: 66% increase in cirrhosis and liver cancer; increase in decompensation, need for transplantation,
and liver-related deaths; liver transplantation crisis—waiting list growing, number of donors unchanged; death
rate and medical costs increasing; effects on Medicare and Social Security; need to treat 50% to 75% of patients to decrease
burden of cirrhosis and decompensative liver disease; aging and weight gain result in increased liver disease; urgency
to identify and treat patients with HCV infections
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| Risk factors for infection: for majority of patients, past intravenous (IV) drug use; active IV drug abuse major risk factor
for new infections, but relatively few new infections now (≈30,000 per year vs ≈300,000 annually in 1980s); “not really”
sexually transmitted (lifetime risk in spouses 3%; test partner once); history of multiple sex partners increases risk
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| Diagnosis: if ALT normal, testing for hepatitis C not necessary (but 30% of patients with hepatitis C have normal ALT levels,
especially if tested only once); ask about history of IV drug use, receipt of blood factors (before 1987) or blood transfusions;
health care workers—3% to 5% risk for infection if stuck with needle used in HCV-infected patient (risk 30% if
patient infected with hepatitis B virus [HBV]; all health workers vaccinated against HBV); no HCV vaccine, but chronic
disease prevented if INF therapy given within 6 mo of infection
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| Cirrhosis: risk of developing complication 3% to 4% per year and cumulative; once complication present (eg, ascites, variceal
bleeding, hepatic encephalopathy), risk of dying ≈50% over 5 yr, and liver transplantation indicated; cirrhosis associated
with hepatitis C major cause of death in HIV population in United States (rapid rate of decompensation); liver
cancer—risk ≈1% per year once patient with hepatitis C develops cirrhosis; risk reduced by INF therapy
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| Extrahepatic manifestations of HCV: some patients develop idiopathic thrombocytopenic purpura, non-Hodgkin’s
B-cell lymphoma, and porphyria cutanea tarda; cryoglobinemia—results in vasculitic rash on lower extremities; HCV
antibody test often negative (use HCV RNA test for diagnosis)
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| Pegylated (PEG)-INF and ribavirin: standard of care; cost-effective (improves with patient compliance); increases
life expectancy by ≈4.5 yr
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| INF therapy: eradicating virus—primary goal; in 1990, 6 mo of treatment resulted in 3% sustained virologic response
(SVR) rate; over time, cure rate improved to >50% with PEG-INF and ribavirin, even in patients with genotype 1; SVR
maintained in >99% of patients at 5 yr; improving histology—secondary goal; SVR rates diminish as patients age, so
important to diagnose and treat as early as possible; younger patients have better SVR than older patients; patients with
milder liver disease have better SVR than patients with cirrhosis; in large studies, ≈11% of patients discontinued therapy
due to side effects, 16% in coinfection studies; therapy requires support and monitoring
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| Future management strategies: faster response to therapy indicates higher likelihood of SVR (eg, chance of cure 90%
if HCV RNA becomes undetectable at 4 wk, 72% if undetectable at 12 wk, 48% if undetectable at 24 wk); stop therapy
early if test results still positive at 24 wk because chance of cure nearly 0%; direct antiviral therapy (protease and polymerase
inhibitors; in development) to be added to standard of care
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| Questions and answers: hepatitis C vaccine—unlikely for at least 5 to 10 yr (“if ever”) because virus mutates and
develops quasi species; currently developing adaptive immune response in which immune system changes as virus mutates
(“they’re just not there”); liver biopsy—not required for all patients; SVR rates for genotypes 2 and 3 usually 85%
to 90% (biopsy often not performed and patients treated with shorter duration [24 wk vs 48 wk] of therapy with lower
dose of ribavirin); perform biopsy at 3-yr intervals in patients with genotype 1 to determine whether patients should be
treated immediately or after 3 to 5 yr when better drugs available; treat patients with moderate or severe fibrosis; tattooing
and body piercing—“soft” risk factor; difficult to prove association with hepatitis C; risk with homemade or prison
tattoos; patient 50 to 60 yr of age with genotype 2 or 3 and cirrhosis—screen for hepatocellular carcinoma at 6-mo
intervals; if patient has signs of cirrhosis (eg, low platelet count, firm liver, enlarged spleen), perform biopsy or treat as
cirrhosis; postoperative risk for hepatitis C—slight increase in risk in patients who undergo surgery or interventional
procedure; risk not related to blood products
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Hepatitis B
| Introduction: prevalence, incidence, morbidity, and mortality increasing due to immigration; chance of chronic disease
when hepatitis B acquired in infancy ≈100%, 3% to 5% when acquired at >5 yr of age; in most Asian countries, prevalence
of vertical transmission 10% to 15%
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| Treatment: HBV can be suppressed, improved, and seroconverted, but not eradicated; approved therapies—standard
INF; lamivudine (Epivir); adefovir (Hepsera); entecavir (Baraclude); PEG-INF; more drugs in development; goals—
normalization of liver tests; DNA suppression; hepatitis B e antigen (HBeAg) loss and seroconversion; surface antigen
(HbsAg) clearance (rare); histologic improvement; lamivudine—rapidly suppresses virus; in study, seroconversion of
HbeAg occurrred in 20% of patients during first year and improved over time; durability of therapy not as good as in hepatitis
C; when drug discontinued after seroconversion, chance of staying in remission 80% to 86%; development of resistance
≈20% per year; because of high rate of resistance, lamivudine no longer used as first-line therapy; adefovir—
HBeAg loss ≈20% per year, seroconversion <20% per year; suppression of virus or normalized liver tests “pretty good”;
rate of developing durability 90% if able to seroconvert HBeAg; cannot discontinue drug if patient not seroconverted;
rate of resistance lower than that of lamivudine, so adefovir used more often, although more expensive; entecavir—
powerful nucleoside analogue; better than lamivudine; risk for resistance 7.4% in lamivudine-resistant patients, 0% in
treatment-naive patients; INF and PEG-INF—durability finite; treat patients for 48 wk; ≈33% clear virus but therapy
difficult (injection; many side effects); most patients prefer oral drugs, but oral drugs associated with resistance; newer
drugs associated with need for indefinite use and high costs ($500/mo)
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| Questions and answers: management of patient with SVR—repeat liver enzymes and HCV RNA test annually;
screening for liver cancer not required unless patient had cirrhosis at start of therapy; patient treated for hepatitis B and
C who develops hyperthyroidism—develops in 1% to 2% of patients treated with INF; hypothyroidism more common;
check thyroid-stimulating hormone (TSH) before and every 12 wk during therapy; hyperthyroidism rare, but INF must be
discontinued (use oral drug in patients with hepatitis B); increased risk for liver cancer with hepatitis B—direct association
between HBV DNA titer and risk for liver cancer; carrier for hepatitis B with normal ALT at slightly increased risk;
high-risk patients with liver disease (typically men with liver damage or cirrhosis) should be screened and suppressed with
drugs; suppressive therapy controversial due to high cost; HCV RNA nondetectable with positive antibody test—
problem with insurance companies because patients labeled with HCV; check liver tests periodically; drug contraindications
in chronic hepatitis B and C—statins safe in patients with hepatitis B or C, or fatty liver; risk for statin-induced
hepatotoxicity no greater than in general population (unless patient has cirrhosis); since patients may be glutathione depleted,
do not exceed 2000 mg daily of acetaminophen (Tylenol); studies unable to prove more advanced liver disease related
to narcotic analgesics in patients with hepatitis C; glutathione supplementation—may be used before giving toxin
(eg, acetaminophen) at high dose; daily use not necessary
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| MILDLY ELEVATED LIVER TRANSAMINASE LEVELS —Martin Black, MD, Emeritus Professor of Medicine, Temple
University School of Medicine, Philadelphia, PA
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| Identifying abnormalities: necroinflammatory—high aminotransferases (serum aspartate aminotransferase [AST]
and ALT); cholestatic—increased alkaline phosphatase and gamma-glutamyl transpeptidase (GGT); transaminases often
mildly increased but rarely exceed 300 IU; patient may have mixed necroinflammatory and cholestatic condition;
nonspecific liver function tests—serum bilirubin usually normal; alkaline phosphatase and GGT may be slightly elevated;
aminotransferases typically <300 IU
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| Aminotransferases: become markedly increased in serum in necroinflammatory liver disease; AST—more sensitive
than ALT in alcohol-induced liver injury but not as specific, eg, can be elevated in muscle diseases and myocardial infarction;
ALT—higher sensitivity in hepatitis C; may be more specific, but also can be affected by muscle injury
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| Diagnostic strategies for elevated aminotransferases: focus on presentation of patient; rule out viral hepatitis;
hepatitis C classically associated with nonspecific liver enzyme abnormalities; rule out alcoholic liver disease (AST typically
exceeds ALT considerably; requires careful history); autoimmune hepatitis—associated with increases in aminotransferase
levels and positive antinuclear antibody and smooth muscle antibody; serum protein electrophoresis shows
hypergammaglobinemia in most patients; rule out hemachromatosis, α1 -antitrypsin deficiency, and Wilson’s disease;
consider nonalcoholic fatty liver disease (NAFLD), particularly in obese diabetic patients who may have fatty liver on
imaging studies
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| Nonalcoholic fatty liver disease: increased echogenicity on ultrasonography often clue to presence of fatty liver (not
sensitive or specific); differentiating nonalcoholic steatohepatitis (NASH) from NAFLD—occur in same clinical setting
(eg, obesity, diabetes); NAFLD more common than NASH; both associated with abnormal liver chemistries and
may occur in patients with normal liver chemistries; prognosis in simple fatty liver disease excellent (independent of increased
mortality from obesity and diabetes); NASH may lead to progressive liver disease, cirrhosis, and liver failure;
distinguish by liver biopsy; noninvasive evaluation of liver disease being introduced
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| Different types of NAFLD: type 1—simply fatty liver; hepatic steatosis; type 2—steatosis; inflammation; type 3—
balloon degeneration; steatosis; inflammation; type 4—fully blown NASH; steatosis; inflammation; Mallory bodies;
pericellular fibrosis; natural history of types 1 and 2 not well-defined but probably do no not progress to cirrhosis; types 3
and 4 may progress, with risk ratio for liver-related death >10; typical appearance of simply fatty liver—extensive
fatty change throughout parenchyma; trichrome stain of biopsy shows little fibrosis, except fibrous tissue around portal
areas; appearance of NASH—presence of fat with balloon degeneration of hepatocytes; hepatocytes with pinkish material
in cytoplasm, representing Mallory’s hyaline; features of NAFLD—inflammation often surrounds hepatocytes that
contain Mallory’s hyaline (satellitosis); increased connective tissue of NASH leads to progression to cirrhosis and eventually
liver failure
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| Prevalence: fatty liver—60% of obese population (10% diagnosed with NASH); NAFLD—steatosis in 17% to 33% of
US population; NASH in 5.7% to 17%; association with metabolic syndrome firmly established
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| Causes of NASH and NAFLD: steatosis—hyperinsulinemia or insulin resistance associated with increased free fatty
acid flux and decreased oxidation; inflammation and fibrosis—oxidative stress involving iron in liver, cytochrome P450
2E1, and increased lipid peroxidation, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)- β, and leptin
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| Reactive oxidant species-mediated toxicity: lipid peroxidation can lead to hepatocyte death, Ito cell activation (results
in collagen deposition, fibrosis, and hepatocyte death), polymorphonuclear infiltration, and cytokeratin crosslinking
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| Management of NASH: weight loss; cytoprotective agents—ursodeoxycholic acid (Actigall) and betaine evaluated;
no evidence for efficacy of antioxidants, vitamin E, betaine, and S-adenosylmethionine (SAM-e); insulin sensitizers
shown effective (metformin shown to reduce insulin resistance); cytokine antagonists—anti-TNF-α agents show some
benefit; pentoxifylline may be helpful; probiotics studied; hypolipidemic drugs also may be useful
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Educational Objectives
| The goal of this program is to educate the listener about hepatitis B and C infections and elevated liver transaminase levels.
After hearing and assimilating this program, the participant will be better able to:
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 | 1. Predict progression of liver damage in patients with hepatitis C, based on patient history and clinical findings.
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| 2. Assess risk factors for hepatitis C.
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| 3. Choose appropriate treatment for hepatitis B.
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| 4. Distinguish nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver disease (NAFLD).
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| 5. Select effective treatment for NASH.
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Discussed on This Program
Acetaminophen (N -acetyl-P -aminophenol; APAP) [Tylenol, several others]
Adefovir dipivoxil [Hepsera]
Betaine anhydrous [Cystadane]
Entecavir [Baraclude]
Interferon alfa-2a, recombinant (rIFN-A; IFLrA) [Roferon-A]
Interferon alfa-2b (recombinant) (IFN-alpha 2; rIFN-⓬ α-2-interferon) [Intron A]
Interferon alfa-2b recombinant and ribavirin combination [Rebetron]
Interferon alfa-n1 [Wellferon]
Interferon alfa-n3 (Human Leukocyte Derived) [Alferon N]
Interferon alfacon-1 [Infergen]
Interferon alpha [Veldona Lozenge]
Interferon beta-1a (recombinant) [Avonex, Rebif]
Interferon beta-1b [Betaseron]
Interferon gamma-1B [Actimmune]
Lamivudine (3TC) [Epivir, Epivir-HBV]
Metformin HCl [Fortamet, Glucophage, Glucophage XR, Riomet]
Pentoxifylline [Trental]
Reduced L-glutathione [Cachexon]
S-adenosylmethionine (SAM-e)
Ursodiol (ursodeoxycholic acid) [Actigall, URSO Forte, URSO 250]
Vitamin E [several trade names]
Suggested Reading
Amarapurkar DN et al: Clinical spectrum and natural history of non-alcoholic steatohepatitis with normal alanine
aminotransferase values. Trop Gastroenterol 25:130, 2004; Aspinall RJ et al: The management of side-effects during
therapy for hepatitis C. Aliment Pharmacol Ther 20:917, 2004; Charlton MR et al: Impact of obesity on treatment of
chronic hepatitis C. Hepatology 43:1177, 2006; de Ledinghen V et al: Should a liver biopsy be done in patients with
subclinical chronically elevated transaminases? Eur J Gastroenterol Hepatol 16:879, 2004; Dixon JB et al: Weight
loss and non-alcoholic fatty liver disease: falls in gamma-glutamyl transferase concentrations are associated with histologic
improvement. Obes Surg 16:1278, 2006; Duseja A et al: Assessment of insulin resistance and effect of metformin in
nonalcoholic steatohepatitis--a preliminary report. Indian J Gastroenterol 23:12, 2004; Gasbarrini G et al: Nonalcoholic
fatty liver disease: defining a common problem. Eur Rev Med Pharmacol Sci 9:253, 2005; Gupta S et al: Hepatitis
B and C virus co-infections in human immunodeficiency virus positive North Indian patients. World J Gastroenterol
12:6879, 2006; Jensen DM et al: Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon
alpha-2a (40 kd)/ribavirin therapy. Hepatology 43:954, 2006; Kiyici M et al: Ursodeoxycholic acid and atorvastatin in
the treatment of nonalcoholic steatohepatitis. Can J Gastroenterol 17:713, 2003; Kunde SS et al: Spectrum of NAFLD
and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology 42:650, 2005;
Liaw YF et al: Factors influencing liver disease progression in chronic hepatitis B. Liver Int 26 Suppl 2:23, 2006;
Pockros PJ et al: Efficacy and safety of two-dose regimens of peginterferon alpha-2a compared with interferon alpha-
2a in chronic hepatitis C: a multicenter randomized controlled trial. Am J Gastroenterol 99:1298, 2004; Pockros PJ: An
urgency to identify and treat chronic hepatitis C. Minerva Gastroenterol Dietol 51:235, 2005; Pockros PJ: Noninvasive
markers of fibrosis in chronic hepatitis patients. J Clin Gastroenterol 40:461, 2006; Shiffman ML et al: Chronic hepatitis
C in patients with persistently normal alanine transaminase levels. Clin Gastroenterol Hepatol 4:645, 2006; Suzuki
A et al: Values and limitations of serum aminotransferases in clinical trials of nonalcoholic steatohepatitis. Liver Int
26:1209, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Pockros is a consultant, receives research support, and/or is on the Speakers’ Bureaus for Bristol-Myers Squibb
Company, Gilead Sciences, Identix Incorporated, and Roche Laboratories.
Dr. Pockros spoke in San Diego, CA, at the 23rd Annual Coronado Summer Conference, Primary Care Medicine: A
Practical Approach, presented August 11-13, 2006, by Scripps Clinic. Dr. Black was recorded in Lancaster, PA, on September
26, 2006, at the 30th Annual Fall Family Practice Review, presented by Temple University School of Medicine,
and Lancaster General Hospital. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in
the production of this program.
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